ICH GCP

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ICH GUIDELINES:

ICH GUIDELINES Kirtikrishna

What is ICH:

What is ICH I nternational C onference On H armonization

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The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)

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It is a unique project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration.

Historical Perspective:

Historical Perspective GCP born in USA – mid 1970s Rigorous IND procedures enforced Various national GCPs USA + Europe + Japan ICH GCP

Six founder members:

Six founder members European Commission European Federation of Pharmaceutical Industries’ Associations (EFPIA) Ministry of Health, Labor and Welfare (MHLW) Japanese Pharmaceutical Manufacturers Association (JPMA) Food & Drug Administration (FDA) Pharmaceutical Research and Manufacturers of America (PhRMA)

Initiation of ICH:

Initiation of ICH Birth of ICH took place at a meeting in April 1990, hosted by the EFPIA in Brussels Europe, Japan and the USA met To plan an International Conference but the meeting also discussed the wider implications and terms of reference of ICH. The ICH Steering Committee which was established at that meeting has since met at least twice a year, with the location rotating between the three regions.

The Triggers:

The Triggers 1930s – Sulfanilamide tragedy Sulfonilamide+diethelene glycol 1960s – Thalidomide tragedy 1960s & 1970s Rapid increase in laws, regulations & guidelines Industry marketing – Global Basic evaluation – similar Detailed technical requirements – varied

Why harmonize?:

Why harmonize? Avoid duplication in tests to conform to different regulatory guidelines More effective utilization of results Timely access of patients to safe and effective new drugs Promote public health Minimize animal testing without compromising safety & effectiveness

Objectives:

Objectives More economical use of human, animal and material resources Elimination of unnecessary delay in global development Make new medicines available while maintaining safeguards on quality, safety, and efficacy, and regulatory obligations to protect public health

The Early Meetings:

The Early Meetings Terms of Reference were agreed and it was decided that the Topics selected for harmonization would be divided into Safety , Quality and Efficacy to reflect the three criteria which are the basis for approving and authorizing new medicinal products It was also agreed that six-party Expert Working Groups (EWGs) should be set up to discuss scientific and technical aspects of each harmonization Topic

Structure of ICH:

Structure of ICH Joint initiative involving both regulators and industry as equal partners in the scientific and technical discussions of the testing procedures which are required to ensure and assess the safety, quality and efficacy of medicines.

Structure of ICH:

Focus of ICH has been on the technical requirements for medicinal products containing new drugs Structure of ICH

Structure of ICH:

Six Parties that are directly involved, Three Observers and IFPMA The Six Parties are the founder members of ICH which represent the regulatory bodies and the research-based industry in the European Union, Japan and the USA. These parties include the EU , EFPIA , MHLW , JPMA , FDA and PhRMA. Structure of ICH

Observers:

Observers WHO, EFTA, and Canada (represented by Health Canada). Important group of non-voting members Acts as a link between the ICH and non-ICH countries and regions.

European Commission - European Union (EU):

European Commission - European Union (EU) European Commission represents the 25 members of the EU Working, through harmonization of technical requirements and procedures, to achieve a single market in pharmaceuticals which would allow free movement of products throughout the EU.

European Commission - European Union (EU):

European Commission - European Union (EU) The European Medicines Agency (EMEA) has been established by the Commission, situated in London. Technical and scientific support for ICH activities is provided by the Committee for Medicinal Products for Human Use ( CHMP ) of the EMEA.

European Federation of Pharmaceutical Industries and Associations (EFPIA):

European Federation of Pharmaceutical Industries and Associations (EFPIA) Situated in Brussels 29 national pharmaceutical industry associations and 45 leading pharmaceutical companies involved in the research, development and manufacturing Much of the Federation's work is concerned with the activities of the European Commission and the EMEA.

Ministry of Health, Labour and Welfare, Japan (MHLW):

Ministry of Health, Labour and Welfare, Japan (MHLW) Responsibilities for approval and administration of drugs, medical devices and cosmetics in Japan. Technical and scientific support for ICH activities are provided by the Pharmaceuticals and Medical Devices Agency (PMDA) and by National Institute of Health Sciences (NIHS) and other experts from academia.

Japan Pharmaceutical Manufacturers Association (JPMA):

Japan Pharmaceutical Manufacturers Association (JPMA) JPMA represents 75 members and 14 committees. Membership includes all the major research-based pharmaceutical manufacturers in Japan. ICH work is coordinated through specialized committees of industry experts who also participate in the Expert Working Groups.

Japan Pharmaceutical Manufacturers Association (JPMA):

Japan Pharmaceutical Manufacturers Association (JPMA) Objectives of JPMA: development of a competitive pharmaceutical industry with a greater awareness and understanding of international issues. JPMA promotes and encourages the adoption of international standards by its member companies.

US Food and Drug Administration (FDA):

US Food and Drug Administration (FDA) Wide range of responsibilities for drugs, biologics, medical devices, cosmetics and radiological products. The largest of the world's drug regulatory agencies Responsible for the approval of all drug products used in the USA.

US Food and Drug Administration (FDA):

US Food and Drug Administration (FDA) Consists of administrative, scientific and regulatory staff organised under the Office of the Commissioner Several Centers with responsibility for the various products which are regulated. Technical advice and experts for ICH work are drawn from the Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER).

Pharmaceutical Research and Manufacturers of America (PhRMA):

Pharmaceutical Research and Manufacturers of America (PhRMA) Represents the research-based industry in the USA. Has 67 companies in membership which are involved in the discovery, development and manufacture of prescription medicines. There are also 24 research affiliates which conduct biological research related to the development of drugs and vaccines.

ICH Observers:

ICH Observers The World Health Organization (WHO) The European Free Trade Association (EFTA), currently represented at ICH by Swiss medic Switzerland Canada, represented at ICH by Health Canada

Three Regions, Six Parties:

Three Regions, Six Parties Observers: WHO, Canada, EFTA

Where is the ICH located?:

Where is the ICH located? ICH does not have "offices" as such because it is a voluntary cooperative effort of cosponsors from the three regions. The ICH Secretariat is based in Geneva. The biennial meetings and conferences of the ICH Steering Committee rotate between the EU, Japan, and the USA.

How is ICH structured?:

How is ICH structured? The ICH structure consists of the ICH Steering Committee, ICH Coordinators, ICH Secretariat and ICH Working Groups.

What is the ICH Steering Committee?:

What is the ICH Steering Committee? Body that governs the ICH, Determines the policies and procedures for ICH, Selects topics for harmonization and Monitors the progress of harmonization initiatives. Each of the six ICH parties has two seats on the ICH Steering Committee. Each of the Observers nominates non-voting participants to attend the ICH Steering Committee Meetings. IFPMA also participates as a non-voting member.

Who are the ICH Coordinators?:

Who are the ICH Coordinators? Fundamental to the smooth running of the ICH and are nominated by each of the six parties. An ICH Coordinator acts as the main contact point with the ICH Secretariat.

What is the ICH Secretariat?:

What is the ICH Secretariat? Operates from the IFPMA offices in Geneva, Switzerland, and provides support to the ICH Steering Committee. Primarily concerned with preparations for, and documentation of, meetings of the Steering Committee as well as coordination of preparations for Working Group (EWG, IWG, Informal WG) and Discussion Group meetings.

What is the ICH Secretariat?:

What is the ICH Secretariat? Information on ICH Guidelines and the general ICH process can be obtained from the ICH Secretariat. Provides administrative support for the GCG, (global co operation group) and is responsible for coordination with the MedDRA Management Board for the international medical dictionary created by the ICH process.

What is an ICH Working Group?:

What is an ICH Working Group? Depending on the type of harmonization activity needed, the Steering Committee will endorse the establishment of one of three types of working group i.e., Expert Working Group (EWG), Implementation Working Group (IWG) or Informal Working Group.

Expert Working Group:

Expert Working Group Develops a harmonized guideline that meets the objectives in the Concept Paper and Business Plan

What is an Implementation Working Group (IWG)?:

What is an Implementation Working Group (IWG)? Established by the Steering Committee to develop Q&As to facilitate the implementation of existing guidelines.

Informal Working Group:

Informal Working Group Developing/finalizing a Concept Paper, as well as developing a Business Plan

Initiation of Harmonization Action:

Initiation of Harmonization Action ICH Regional Guideline Workshops; Other regional and international conferences, Workshops and symposia dealing with R&D and regulatory affairs; Recognized Associations, Federations and Societies which represent scientific and technical professionals concerned with the development, testing and registration of medicines

How is a new topic proposed?:

How is a new topic proposed? When one of the six parties feels that it has a suitable topic for harmonization, the party prepares a proposal (or concept paper) that outlines the subject, the need for harmonization, the anticipated effort and timetable for completion, and a recommendation on the type of working group required. The Steering Committee discusses intensively before deciding whether or not a topic requires harmonization.

ICH Concept Paper:

ICH Concept Paper Trigger of all ICH harmonization activities Describes the perceived problem and the issues to be resolved

Categories of ICH Harmonisation Activities:

Categories of ICH Harmonisation Activities Category Type of procedure 1 Formal ICH procedure 2 Q&A procedure 3 Revision procedure 4 Maintenance procedure

Formal ICH Procedure (Category 1):

Formal ICH Procedure (Category 1) Corresponds to the original ICH process and was used for more than a decade, Now includes some additional explanation on each activity

Step 1: Consensus building:

Step 1: Consensus building When the Steering Committee adopts a Concept Paper as a new topic, then the process of consensus building begins. An extended EWG or original EWG shall be established consultation will be carried out by correspondence, using fax and e-mail

Step 2: Confirmation of six-party consensus:

Step 2 : Confirmation of six-party consensus Steering Committee agrees, based on the report of the EWG, that there is sufficient scientific consensus on the technical issues for the draft guideline or recommendation to proceed to the next stage of regulatory consultation

Step 3: Regulatory Consultation and Discussion:

Step 3 : Regulatory Consultation and Discussion a) Regional regulatory consultation subject of normal wide-ranging regulatory consultation in the three regions b) Discussion of regional consultation comments EWG who organized the discussion for consensus building will be resumed Step 4 Experts Document is signed by the EWG regulatory experts

Where complete consensus has not been achieved :

Where complete consensus has not been achieved Steering Committee may then: Allow an extension of the time frame, if the EWG can give assurances that consensus could be reached within a short, specified period; Decide to abandon the current draft and resume the discussion from Step 1 ; Decide to suspend or abandon the harmonization project.

Step 4: Adoption of an ICH Harmonised Tripartite Guideline:

Step 4 : Adoption of an ICH Harmonised Tripartite Guideline When the Steering Committee agrees, on the basis of the report from the regulatory Rapporteur of the EWG, that there is sufficient scientific consensus on the technical issues

Step 5: Implementation:

Step 5 : Implementation regulatory implementation Information on the regulatory action taken and implementation dates are reported back to the Steering Committee and published by the ICH Secretariat on the ICH website.

Current Status of Harmonization: (over 50 harmonized guidelines) :

Current Status of Harmonization: (over 50 harmonized guidelines) Efficacy - 12 topic headings/14 guidelines Safety - 7 topic headings/14 guidelines Quality - 7 topic headings/19 guidelines Medical Dictionary - MedDRA Electronic Standards - ESTRI, E2B Industry proposed taking the information generated by these harmonized guidances and putting it the same order

What are the Products of ICH?:

What are the Products of ICH? Over 50 harmonized guidelines aimed at eliminating duplication in the development and registration process, so that a single set of studies can be generated to demonstrate the quality, safety and efficacy of a new medicinal product. Include CTD,- describes the common format for the preparation of a well-structured CTD for applications that will be submitted to regulatory authorities.

What are the Products of ICH?:

What are the Products of ICH? Facilitate international electronic communication through Electronic Standards for the Transfer of Regulatory Information ( ESTRI ) that will meet the requirements of the pharmaceutical companies and regulatory authorities. Electronic Common Technical Document (e CTD) MedDRA Terminology

How are the ICH guidelines used?:

How are the ICH guidelines used? Industry and governments in ICH and non-ICH countries can use the ICH guidelines to address technical issues during the product development process. Teaching tools. Can reduce duplication in meeting technical requirements, thereby saving financial and material resources.

The topics:

The topics Safety (S) Dealing with in vitro & in vivo pre clinical testing Quality (Q) Chemical & Pharmaceutical QA Stability, Specifications, Analytical Efficacy (E) Clinical studies in humans Multidisciplinary (M) Terminology Electronic standards Common Technical Documents

Safety Guidelines(animal studies/Pre clinical studies ):

Safety Guidelines(animal studies/Pre clinical studies ) Carcinogenicity Studies Genotoxicity Studies Toxicokinetics and Pharmacokinetics Toxicity Testing Reproductive Toxicology Biotechnological Products Pharmacology Studies Immunotoxicology Studies Joint Safety/Efficacy  (Multidisciplinary) Topic

Carcinogenicity Studies :

Carcinogenicity Studies S1A Need for Carcinogenicity Studies of Pharmaceuticals S1B Testing for Carcinogenicity of Pharmaceuticals S1C(R1) New title: Dose Selection for Carcinogenicity Studies of Pharmaceuticals & Limit Dose

Genotoxicity Studies :

Genotoxicity Studies S2A Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals

Toxicokinetics and Pharmacokinetics :

Toxicokinetics and Pharmacokinetics S3A Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies S3B Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies

Toxicity Testing :

Toxicity Testing S4 Duration of Chronic Toxicity Testing in Animals (Rodent and Non Rodent Toxicity Testing)

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S5(R2) New title: Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals

Pharmacology Studies :

Pharmacology Studies S7A Safety Pharmacology Studies for Human Pharmaceuticals S7B The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals

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S8 Immunotoxicity Studies for Human Pharmaceuticals M3(R1) Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals

Quality Topics (manufacturing):

Quality Topics (manufacturing) Those relating to chemical and pharmaceutical Quality Assurance.

Quality Topics:

Quality Topics Stability Analytical Validation Impurities Pharmacopoeias Quality of Biotechnological Products Specifications Good Manufacturing Practice Pharmaceutical Development Quality Risk Management

Stability :

Stability Q1A(R2) Stability Testing of New Drug Substances and Products Q1B Stability Testing : Photo stability Testing of New Drug Substances and Products Q1C Stability Testing for New Dosage Forms Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products Q1E Evaluation of Stability Data Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV

Analytical Validation :

Analytical Validation Q2(R1) New title: Validation of Analytical Procedures: Text and Methodology

Impurities :

Impurities Q3A(R2) Impurities in New Drug Substances Q3B(R2) Impurities in New Drug Products Q3C(R3) Impurities: Guideline for Residual Solvents

Pharmacopoeias:

Pharmacopoeias Q4 Pharmacopoeias Q4A Pharmacopoeia Harmonization Q4B Regulatory Acceptance of Analytical Procedures and/or Acceptance Criteria (RAAPAC)

Quality of Biotechnological Products :

Quality of Biotechnological Products Q5A(R1) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin Q5B Quality of Biotechnological Products : Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein Products Q5C Quality of Biotechnological Products : Stability Testing of Biotechnological/Biological Products

Quality of Biotechnological Products:

Quality of Biotechnological Products Q5D Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products Q5E Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process

Specifications :

Specifications Q6A Specifications : Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (including Decision Trees) Q6B Specifications : Test Procedures and Acceptance Criteria for Biotechnological/Biological Products

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Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients Q8 Pharmaceutical Development Q9 Quality Risk Management

Efficacy guidelines (Clinical studies):

Efficacy guidelines (Clinical studies) Clinical Safety Clinical Study Reports Dose-Response Studies Ethnic factors Good Clinical Practice Clinical Trials on special population Guidelines for Clinical Evaluation by Therapeutic Category Clinical Evaluation-( statistical consideration) Pharmacogenomics

Clinical Safety :

Clinical Safety E1 The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life Threatening Conditions E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting E2B(R3) Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports E2C(R1) Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting E2E Pharmacovigilance Planning

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E3 Structure and Content of Clinical Study Reports E4 Dose-Response Information to Support Drug Registration E5(R1) Ethnic Factors in the Acceptability of Foreign Clinical Data E6(R1) Good Clinical Practice

Clinical Trials:

Clinical Trials E7 Studies in Support of Special Populations: Geriatrics E8 General Consideration of Clinical Trials E9 Statistical Principles for Clinical Trials E10 Choice of Control Group and Related Issues in Clinical Trials E11 Clinical Investigation of Medicinal Products in the Pediatric Population

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E12 Principles for Clinical Evaluation of New Antihypertensive Drugs E14 The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs E15 Terminology in Pharmacogenomics

M "Multidisciplinary" Topics:

M "Multidisciplinary" Topics Cross-cutting Topics which do not fit uniquely into one of the above categories. M1: Medical Terminology (MedDRA) M2: Electronic Standards for Transmission of Regulatory Information (ESTRI) M3: Timing of Pre-clinical Studies in Relation to Clinical Trials M4: The Common Technical Document (CTD) M5: Data Elements and Standards for Drug Dictionaries

What is MedDRA?:

What is MedDRA? Medical Dictionary for Regulatory Activities Terminology (MedDRA) It provides an international medical dictionary applicable to all phases of product development. The MedDRA Maintenance and Support Services Organization (MSSO) holds a contract with the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) as a trustee of the Steering Committee to maintain and develop the terminology to meet Users' needs.

Medical Terminology:

Medical Terminology Designed to support the classification, retrieval, presentation and communication of medical information throughout the medical product regulatory/life cycle Its goal is to provide a comprehensive and specific terminology to help standardize, facilitate and simplify regulatory processes

ICH M2 ESTRI :

ICH M2 ESTRI Established during the ICH meeting 1994 in Brussels to facilitate international electronic communication by evaluating and recommending, open and non-proprietary - to the extent possible - Electronic Standards for the Transfer of Regulatory Information (ESTRI) that will meet the requirements of the pharmaceutical companies and regulatory authorities.

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First Specification developed by the M2 EWG to follow the Step process was the Individual Case Safety Report (ICSR), created as the electronic message for the ICH E2BM The second Specification developed by the M2 EWG was the Electronic Common Technical Document (eCTD) created as the electronic message for the CTD developed by the ICH M4. The most recent Specification developed by the M2 EWG is the Study Tagging File (STF) Specification . The STF is supplemental to the eCTD.

M3 Timing of Pre-clinical Studies in Relation to Clinical Trials:

M3 Timing of Pre-clinical Studies in Relation to Clinical Trials Principles for development of non-clinical strategies on the timing of toxicity studies in relation to conduct of clinical trials

M4 The Common Technical Document:

M4 The Common Technical Document CTD is an agreed upon common format for the “modular” presentation of summaries, reports and data Incorporates relevant ICH guidelines as building blocks and puts them in the same order for submission to ICH regions

M4 The Common Technical Document:

M4 The Common Technical Document Harmonized structure and format for new product applications Four sections Application organization Quality section Safety section Efficacy section e-CTD

The CTD Triangle:

The CTD Triangle Module 1 Regional Admin Information Module 3 Quality Module 4 Nonclinical Study Reports Module 5 Clinical Study Reports Quality Overall Summary Nonclinical Summary Nonclinical Overview Clinical Summary Clinical Overview Module 2 NOT Part of the CTD The CTD

Annex:Granularity Document:

Annex:Granularity Document Series of standards for the physical construction of CTD submissions Applicable to both paper & e-CTD Pagination, use of section numbers, use of tab dividers What to include in TOC for each module

M5 Data Elements and Standards for Drug Dictionaries :

M5 Data Elements and Standards for Drug Dictionaries Lack of standards related to core sets of medicinal product information and medicinal product terminology Applies in particular to the area of pharmacovigilance This document provides guidance on the harmonized standards that are being proposed by the ICH M5 EWG to facilitate the exchange and practical use of medicinal product data by regulators and pharmaceutical industry.

M5 Data Elements and Standards for Drug Dictionaries:

M5 Data Elements and Standards for Drug Dictionaries Routes of Administration Controlled Vocabulary Units and Measurements Controlled Vocabulary

The Impact of ICH:

The Impact of ICH Enhanced patient safety Streamline development programs Common quality standards Reduce resource requirements Forum for communication Opportunity for industry & regulators to sit across the table Discuss drug development procedure with a common goal of identifying best scientific practice & applying the same uniformly across the globe

ICH in future:

ICH in future Timely access of innovations for patients globally Changing environment – Regulations & Science Maintenance & Implementation – CTD & GLs Pharmacovigilance Transparency – Global Cooperation, Large Conference

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